¹Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville; and St Jude Children's Research Hospital, Memphis, Tenn

Correspondence: Richard B. Kim, MD, 572 MRB-1, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602 E-mail: richard.kim@mcmail.vanderbilt.edu

^*Supported in part by United States Public Health Service grants GM31304, GM54724, GM60346, ES05851, and RR00095 and by the American Lebanese Syrian Associated Charities (ALSAC).

Received 23 March 2001; Accepted 23 May 2001.

Abstract

MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1ast;2) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1ast;1) or a site-directed Ser893 mutation (MDR1ast;2) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1ast;1 and MDR1ast;2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level–time curve being almost 40% greater in the ^*1/^*1 genotype compared with the ^*2/^*2 and the ^*1/^*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1ast;2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.